The mineral calcium is an important human dietary component. Calcium is required for adequate bone formation and maintenance, as well as for diverse metabolic functions. These diverse metabolic functions of calcium are incompletely understood but likely to involve, at least in part, the alteration and functional control of proteins such as enzymes, and of hormones that regulate bone metabolism.
An assurance of adequate dietary calcium intake is thus important for normal development, metabolism and maintenance. Dietary calcium intake alone however is insufficient to assure that adequate calcium levels are available for required body functions. Dietary calcium must be absorbed from the digestive tract before it may be utilized. The efficiency of calcium absorption is determined by several factors, including the physiological status of the patient and the particular chemical form of ingested calcium. However, a part of the absorbed calcium is eliminated in urine, which poses a problem for certain subjects who are prone to the formation of calcium-containing kidney stones (calcium nephrolithiasis).
Thus, the amount of calcium intake and efficiency of calcium absorption could influence two clinical conditions, osteoporosis and calcium nephrolithiasis.
A condition of particular relevance to calcium dietary requirement is osteoporosis. Osteoporosis, a condition characterized by decreases in bone mass, renders bones more fragile and susceptible to fracture. The increasingly older population of this country, since osteoporosis is usually an age-related phenomenon, further accentuates the significance of this condition. Postmenopausal women are generally agreed to be most susceptible to osteoporosis. These women have an impaired production of active vitamin D compound which normally stimulates calcium absorption. Because of this disturbed physiological status, they cannot absorb calcium efficiently from intestines, resulting in "negative calcium balance" (net loss of calcium from bone). Thus, they require an increased calcium intake to maintain a zero calcium balance and prevent calcium loss from bone (Heaney et al., J. Lab. Clin. Med., 1978, Vol. 92, No. 6, pp. 953-963). The NIH Concensus Development Conference on Osteoporosis (April 2-4, 1984) concluded that "an increase in calcium intake to 1,000 to 1,500 mg a day would reduce the incidence of osteoporosis in postmenopausal women". The Conference report also recommended calcium tablets "for those unable to take 1,000 to 1,500 mg calcium by diet". Increased calcium intake for elderly men was also recommended since their actual calcium intake may be less than that required to prevent negative calcium balance.
Because of frequent aversion to milk in elderly persons, various calcium supplements have been used to increase calcium intake. However, no distinction between calcium supplements was recognized (Consensus Development Conference on Osteoporosis). Skillman concluded "most salts of calcium are acceptable as calcium supplements" (Skillman, T. G., Osteoporosis, Consultant, Feb. 1984, pp. 153-165).
Studies of the present applicant suggest that calcium bioavailability, or the amount of calcium available for intestinal absorption, may vary among different calcium preparations (Nicar and Pak (1985) J. Clin. Endocrin. & Metab. V. 61, pp. 391-393). These variations result from differing properties such as the low aqueous solubility of some salts (calcium carbonate and calcium phosphate) and the ability of some anionic components (such as citrate) to form soluble complexes with calcium. The aqueous solubility of many calcium salts decreases as pH increases. In the normally acid environment of gastric juice, most calcium salts dissolve and become bioavailable except at very high dosages. However, when gastric acidity is abnormally low resulting in a high pH (as in achlorhydria or in some elderly persons who have defective acid production), calcium bioavailability from calcium carbonate and calcium phosphate may be low because of their incomplete gastric dissolution. When calcium salts of lactate, citrate and carbonate are given, the anions released may tend to neutralize the gastric juice and impair further solubility of calcium salts. Calcium absorbability may also depend on the type and extent of soluble complexation of calcium. The calcium complex (such as calcium citrate) itself may be absorbable.
Thus, in postmenopausal women and elderly men with impaired efficiency of intestinal calcium absorption, the provision of calcium supplementation with a high bioavailability due to particular chemical form should facilitate correction of physiologically abnormal calcium absorption, thus preventing negative calcium balance and retarding osteoporosis development.
In certain individuals however, dietary calcium supplementation may increase urinary calcium and lead to formation of calcium-containing kidney stones (nephrolithiasis).
Kidney stone formation may result from a number of conditions, one of which is the presence of undue amounts of calcium in urine. Pak et al (N. Engl. J. Med. (1974) Vol. 290 pp. 175 to 180) have shown that urinary calcium levels and renal calcium stone formation are decreased when patients with a history of recurrent calcium nephrolithiasis are fed on low calcium diets and treated orally with cellulose phosphate. Pak (Urolithiasis Research (1976) ed. by H. Fleisch et al., Phenum Pub. Co., N.Y., N.Y. pp. 213-224) demonstrated that when patients with absorptive hypercalciuria are fed calcium gluconate, they exhibited increased urinary calcium, leading to an increased activity product ratio, a measure of the degree of urinary calcium oxalate saturation. Thus, calcium supplementation made them more prone to form kidney stones, since their urine became more supersaturated with respect to a common stone salt (calcium oxalate).
The risk of calcium nephrolithiasis in many postmenopausal women and in elderly men is probably small. Because they have physiologically impaired ability to absorb calcium, their urinary calcium may not increase sufficiently to cause calcium stone formation following calcium supplementation. However, some of these persons may have high urinary calcium to begin with or have relatively normal calcium absorption (Sakhaee, K. J. Clin. Endo. Metab. Vol. 61, 1985, pp. 368-373). In such persons, calcium supplementation may cause kidney stones. Early postmenopausal women or pre-menopausal women with adequate calcium absorption may be similarly at risk. This danger was recognized by the Consensus Development Conference on Osteoporosis which warned that excessive calcium intake "could cause urinary tract stones in susceptible people".
Supplementation of the diet with calcium appears to be an important step in the prevention of osteoporosis in postmenopausal women and elderly men who have physiologically insufficient calcium absorption from intestines. However, such calcium supplementation may cause the undesirable side effect of calcium-containing kidney stones, especially in persons with relatively normal intestinal calcium absorption such as in pre-menopausal or early postmenopausal women.
An optimum calcium supplement should exhibit superior calcium bioavailability in order to best avert negative calcium balance, and should also reduce the risk for kidney stone formation. Thus, a method of providing efficiently absorbed calcium while precluding calcium nephrolithiasis is needed.